Synthesis of (-)-laulimalide: An agent for microtubule stabilization

Article abstract of DOI:10.1016/S0040-4039(02)00907-3

An enantioselective synthesis of (-)-laulimalide is described. Key reactions include a convergent allylation coupling reaction, asymmetric conjugate addition, the allenylstannane Ferrier reaction and a chelation-controlled alkenylzinc addition as the basi

Full text of DOI:10.1016/S0040-4039(02)00907-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4841–4844
Synthesis of (−)-laulimalide: an agent for microtubule
stabilization
David R. Williams,* Liang Mi, Richard J. Mullins and Ryan E. Stites
Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, IN 47405-7102, USA
Received 22 April 2002; accepted 7 May 2002
Abstract—An enantioselective synthesis of (−)-laulimalide is described. Key reactions include a convergent allylation coupling
reaction, asymmetric conjugate addition, the allenylstannane Ferrier reaction and a chelation-controlled alkenylzinc addition as
the basis for stereocontrol in critical elements of chirality. © 2002 Elsevier Science Ltd. All rights reserved.
allenylstannane Ferrier reaction.11 Herein, we report
our efforts for the synthesis of (−)-laulimalide.
Laulimalide, (1) a novel 20-membered macrolactone,
was isolated from the marine sponges Cacaspongia
mycofijiensis,1 Hyatella sp.,2 and Fasciospongia rimosa.3
Efforts by Jefford and coworkers established the abso-
lute configuration of 1 via X-ray diffraction studies.3 It
has been reported that laulimalide displays antitumor
potency comparable to paclitaxel against breast and
ovarian cancer cell lines, as well as potent activity
against P388 murine lymphoma, A549 human lung,
HT-29 human colon, and MEL28 tumor cell lines.4 The
mechanism for this cytotoxicity is attributed to the
ability of laulimalide to stabilize and promote tubulin
polymerization, leading to the formation of abnormal
mitotic spindles, mitotic arrest and the initiation of
apoptosis.4 Significantly, laulimalide retains its activity
in the multi-drug resistant SKVLB-1 cell line, suggest-
ing some difference in the mode of action compared to
Taxol®. While paclitaxel is a substrate for P-glyco-
protein export, laulimalide does not exhibit this behav-
ior, suggesting new opportunities for chemotherapy.5
As a result, laulimalide has received recent attention as
an important target, resulting in four reports of total
synthesis.6 Additionally, a number of groups have
reported the preparation of components related to this
objective, and the formation of relevant analogs.7
Our approach towards the synthesis of laulimalide
relies on coupling of allylsilane 2 and aldehyde 3 (Fig.
1). The synthesis began with the asymmetric conjugate
addition reaction of the N-enoyloxazolidinone 4 with
the allylcopper species formed under Yamamoto
conditions12 (Scheme 1). The high diastereofacial selec-
tivity of this reaction established the chirality at C11 in
2, and subsequent methanolysis with oxazolidinone
cleavage and ozonolysis provided the pure aldehyde 5.10
Construction of the pyran ring was carried out by
utilization of an asymmetric hetero-Diels–Alder
cycloaddition of 5 and the Danishefsky diene13 6 in the
presence of 5 mol% of Jacobsen catalyst 7.14 After some
H
O
HO
H
O
OH
H
O
14
20
11
H3C
O
1
4
H
H
O
CH3
1
Our aims for the synthesis of laulimalide were inspired
by a series of ongoing investigations in our laborato-
ries. Strategies to be explored through synthesis
included asymmetric allylation,8 chelation-controlled
alkenylzincate addition,9 asymmetric conjugate addition
with Yamamoto organocopper reagents10 and the
TMS
H
O
14
O
H
OTBS
15
H
11
H3C
H
O
+
20
4
H
H
O
OPMB
1
OPMB
CH3
2
3
* Corresponding author. Tel.: +1-812-855-6629; fax: +1-812-855-8300;
e-mail: williamd@indiana.edu
Figure 1. Retrosynthetic analysis.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00907-3

4842
D. R. Williams et al. / Tetrahedron Letters 43 (2002) 4841–4844
The synthesis of the C15–C28 component 3 as illustrated
in Scheme 2 commenced with silyl ether 11.19 The
hydrolysis of the ketal 11 posed problems due to the
reactivity of the allylic silyl ether. By adapting a proce-
dure which we had devised for studies of the total
synthesis of (+)-phyllanthocin,20 the Lewis acid-pro-
moted ketal exchange at −78°C with 1,3-propanedithiol
in methylene chloride led to the desired diol for conver-
sion to optically active aldehyde 12. Selective protection
of the secondary alcohol was accomplished by ketaliza-
tion with p-anisaldehyde dimethyl acetal and DIBAL
reduction at −78°C with subsequent oxidation yielding
12. Thus, our strategy for the formation of the vicinal
(C19–C20) syn-diol of 1 was designed to effect a chela-
tion-controlled nucleophilic addition of an E-alkenyl-
zincate with the a-alkoxyaldehyde 12 as previously
explored in these laboratories.7b,9 However, the multi-
tasking operations of formation of the E-alkenylhalide,
lithium–halogen exchange, introduction of dimethylzinc
and 12, offset the advantages of higher diastereoselec-
tivity. Utilization of a one-pot procedure, as devised by
Wipf and coworkers,21 employed hydrozirconation of a
terminal alkyne22 for in situ transmetallation with
dimethylzinc to yield alkenylzinc species 13, which
underwent smooth addition to 12. Preparative scale
1. 1,3-propanedithiol,
20
TBSO
BF3•OEt2, –78 °C, 80%
O
15
2. p-CH3OC6H4C(OCH3)2,
O
11
TsOH, CH2Cl2
3. DIBAL-H, OEt2, –78 °C,
77% (2 steps)
4. TPAP, NMO, CH2Cl2, 60%
Scheme 1. Synthesis of the C1–C14 component.
H
MeZn
O
13
20
CHO
CH3
experimentation with the preparation of catalyst 7 and
the Diels–Alder conditions, we reproducibly obtained
the pyranone 8 in 91% yield as the major component of
an inseparable mixture of two C9 diastereomers (7.5:1
ratio).15 While chromatographic separation of these
isomers was not feasible on a preparative scale until
later in the scheme, the mixture was used without
difficulty in the ensuing steps.
TBSO
TBSO
CH2Cl2, –78 °C → –20 °C
15
12
OPMB
84%, (4:1)
15
1. TBSOTf, iPr2NEt, CH2Cl2,
OH
0 °C, 88%
H
O
2. Cl2(PCy3)2Ru=CHPh (10 mol%),
CH2Cl2, reflux, 60%
20
OPMB
A stereoselective Luche reduction and acetylation pro-
vided the equatorial acetate 9. Efficient installation of
the C1–C4 carbon component was achieved via the
Lewis acid-catalyzed acetate solvolysis of 9 to form an
intermediate oxocarbenium species for axial addition of
the allenylstannane 10.16 The use of reactive allenyl-
stannane 10 directly introduced the propargylic ether
for subsequent oxidation to the desired acetylenic car-
boxylic acid. The stereochemical features of the trans-
2,6-disubstituted dihydropyran ring were confirmed by
14
TBSO
CH3
O
15
OTBS
H
1. PPTS, EtOH, 75%
20
OPMB
15
2. tBuOOH, (+)-DET, Ti(OiPr)4,
CH2Cl2, –20 °C, 94%
3. Dess-Martin periodinane,
CH3
H
CH2Cl2, 88%
O
H
OHC
OTBS
14
1
H
the nOe observed in H NMR studies of the C4 propar-
O
20
gylic methylene protons and the C9 methine hydrogen.
Preparation of the C1–C14 component 2 was finalized
through the cerium chloride mediated double addition
of TMSCH2MgBr,17 which resulted in spontaneous
Peterson elimination to provide the allylsilane moiety.18
OPMB
3
CH3
Scheme 2. Synthesis of the C15–C27 component.

D. R. Williams et al. / Tetrahedron Letters 43 (2002) 4841–4844
4843
Scheme 3. Completion of the synthesis.
reactions gave 84% yield of
In summary, we have described an efficient and highly
convergent strategy for the synthesis of (−)-laulimalide.
The key coupling of two fully functionalized compo-
nents was accomplished via a stereocontrolled allylation
strategy, which incorporated the C16–C17 trans-epoxide
at an early stage in the synthesis pathway. The carbon-
Ferrier process has demonstrated the use of an allenic
stannane, leading to the direct attachment of a propar-
gyl substituent at C1 of the dihydropyran nucleus. Our
scheme provides flexibility and efficiency for the design
of numerous derivatives of biological interest for con-
tinuing studies.31
a
mixture of C20
diastereomers 14 (4:1 ratio).23,24 Following the silyl
ether protection of 14, a ring-closing metathesis was
accomplished using Grubbs’ catalyst.25 At this point,
the C20 diastereomers were conveniently separated by
flash silica gel chromatography to yield pure 15. Selec-
tive cleavage of the primary silyl ether, followed by
Sharpless asymmetric epoxidation26 and Dess–Martin
oxidation provided the aldehyde 3 for coupling studies.
The completion of our synthesis of laulimalide, shown
in Scheme 3, was proposed with the key element of a
Felkin–Ahn addition of the allylic silane 2 to the enan-
tiopure a,b-epoxyaldehyde 3. The successful application
of the allylation strategy, as well as the diastereofacial
selectivity, was anticipated owing to our related studies
leading to the syntheses of amphidinolides K and P.8b,8c
In the event, the use of BF3·OEt2 promoted the nucle-
ophilic coupling of 2 and 3 at −78°C to yield a single
homoallylic alcohol, which resulted in 16 upon protec-
tion as the tert-butyldimethylsilyl (TBS) ether.27 Oxida-
tive DDQ cleavage of the C1 and C19
para-methoxybenzyl ethers gave a diol (76%), which
was chemoselectively transformed to the desired seco-
acid 17. The crude carboxylic acid was used directly for
Yamaguchi macrolactonization28 to provide the macro-
cyclic acetylenic ester 18 in 53% overall yield (three
steps) from the precursor diol. Lindlar reduction of 18
gave the desired 20-membered Z-enoate in 95% yield as
Acknowledgements
The authors gratefully acknowledge support from the
National Institutes of Health (GM41560).
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